Available online http://ccforum.

com/content/9/2/177

Review

Bench-to-bedside review: Ventilator strategies to reduce lung

injury lessons from pediatric and neonatal intensive care
Sally H Vitali1 and John H Arnold2
1Assistant, Department of Anesthesia and Critical Care Medicine, Childrens Hospital Boston, and Instructor in Anaesthesia, Harvard Medical School,
Boston, Massachusetts, USA
2Senior Associate, Department of Anesthesia and Critical Care Medicine, Childrens Hospital Boston, and Associate Professor of Anaesthesia
(Pediatrics), Harvard Medical School, Boston, Massachusetts, USA

Corresponding author: John H Arnold, john.arnold@childrens.harvard.edu

Published online: 4 November 2004

This article is online at http://ccforum.com/content/9/2/177
2004 BioMed Central Ltd

Critical Care 2005, 9:177-183 (DOI 10.1186/cc2987)

Abstract

the adult population in their efforts to optimize outcomes in

patients requiring mechanical ventilation.

As in the adult with acute lung injury and acute respiratory distress
syndrome, the use of lung-protective ventilation has improved
outcomes for neonatal lung diseases. Animal models of neonatal
respiratory distress syndrome and congenital diaphragmatic hernia
have provided evidence that gentle ventilation with low tidal
volumes and open-lung strategies of using positive end-expiratory
pressure or high-frequency oscillatory ventilation result in less lung
injury than do the traditional modes of mechanical ventilation with
high inflating pressures and volumes. Although findings of
retrospective studies in infants with respiratory distress syndrome,
congenital diaphragmatic hernia, and persistent pulmonary
hypertension of the newborn have been similar to those of the
animal studies, prospective, randomized, controlled trials have
yielded conflicting results. Successful clinical trial design in these
infants and in children with acute lung injury/acute respiratory
distress syndrome will require an appreciation of the data
supporting the modern ventilator management strategies for infants
with lung disease.

Fortunately, the practice of lung-protective ventilation is not at

all revolutionary in neonatal and pediatric intensive care units,
where protective modalities such as continuous positive
airway pressure (CPAP), high-frequency oscillatory ventilation
(HFOV), and extracorporeal membrane oxygenation (ECMO)
have been widely utilized over the past 20 years. In the same
way that children are not just small adults, as the saying
goes, they are also not just large babies. Nevertheless, a
thoughtful review of the evidence supporting current
ventilator strategies used for neonatal respiratory distress
syndrome (RDS), persistent pulmonary hypertension of the
newborn (PPHN), and congenital diaphragmatic hernia
(CDH) will help to guide the use of lung-protective strategies
in the pediatric intensive care unit.

Introduction

Respiratory distress syndrome in the preterm

neonate

Although the first animal studies demonstrating the

phenomenon of ventilator-induced lung injury (VILI) were
published in the mid-1970s [1], it took 25 years to translate
that information into a practice paradigm for treating adults
with acute lung injury (ALI) and acute respiratory distress
syndrome (ARDS) that is supported by a well designed,
randomized, controlled clinical trial [2]. In the pediatric
population, the smaller number of absolute cases of
ALI/ARDS and lower mortality rate make it unlikely that a
similar randomized, controlled clinical trial will be completed
in the near future. For the moment, pediatric intensivists must
extrapolate clinical trial results and ventilator algorithms from

Nowhere is the potential harm caused by mechanical

ventilation more evident than in the premature lung, which at
birth is subject to the consequences of supplemental oxygen
and mechanical ventilation. Although the ability to replace
surfactant has reduced the severity of RDS and has
permitted improved survival for even the most premature
infants, the percentage of surviving infants who develop
neonatal chronic lung disease (CLD) remains high [3,4]. As in
adults with ARDS, the search for interventions that will
improve outcomes in RDS has focused on determining the
safest and most lung-protective means of providing
mechanical ventilation to these infants.

ALI = acute lung injury; ARDS = acute respiratory distress syndrome; BPD = bronchopulmonary dysplasia; CDH = congenital diaphragmatic
hernia; CLD = chronic lung disease; CMV = conventional mechanical ventilation; CPAP = continuous positive airway pressure; ECMO = extracorporeal membrane oxygenation; HFOV = high-frequency oscillatory ventilation; iNO = inhaled nitric oxide; PEEP = positive end-expiratory pressure;
PPHN = persistent pulmonary hypertension of the newborn; RDS = respiratory distress syndrome; VILI = ventilator-induced lung injury.

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Animal studies
Although preterm lung volumes are small, significant inflation
pressures are often necessary during resuscitation because of
surfactant deficiency, immature structure, and fetal lung fluid.
Animal studies in premature lambs have found that initial
resuscitation with high tidal volumes augments abnormalities
of lung mechanics [57], increases edema formation [810],
increases inflammatory cytokine production [10], worsens
histopathology [5,6], and leads to decreased surfactant
production [11], even when used in combination with
surfactant therapy [57,11]. The potential for overdistension is
greater in the neonate because of a very compliant chest wall,
which permits lung expansion beyond total lung capacity.

Another important mechanism of VILI in the preterm lung is

the repetitive opening and closing of atelectatic alveolar units,
which is more pronounced in the preterm infant because of
surfactant deficiency. A strategy to reduce this effect is the
open-lung strategy of maintaining lung volumes with positive
end-expiratory pressure (PEEP) or HFOV. McCulloch and
coworkers [12] compared HFOV using high and low mean
airway pressures in rabbits after saline lavage-induced
surfactant deficiency, and found that maintainence of lung
volumes significantly improved lung compliance and reduced
hyaline membrane formation. In the preterm lamb and
newborn piglet surfactant washout models, an open-lung
strategy improved histologic evidence of collapse, preserved
lung function, improved surfactant function, and reduced
inflammation [1317].
Before the advent of surfactant therapy, many surviving
premature infants developed bronchopulmonary dysplasia
(BPD) a disease described by Northway and coworkers
[18] in 1967 as one of alveolar and bronchiolar fibrosis. After
the advent of surfactant therapy and gentler ventilation
techniques, the lung pathology in those infants who continue
to require pulmonary support after RDS is characterized by
arrested alveolar development with less fibrotic change [19].
This new BPD with deficient alveolarization has been termed
CLD of infancy, defined clinically as dependence on
supplemental oxygen at postconceptual age 36 weeks.
Recently, preterm lamb and baboon models that manifest
abnormal alveolarization after surfactant and 34 weeks of
mechanical ventilation have been developed [20,21]. Studies
in these animal models have provided evidence that, in
addition to improving other markers of lung injury, lungprotective ventilation improves alveolarization and lung
development [20,22]. This finding has added fuel to the
search for the most lung-protective ventilation strategies for
extremely premature infants.

178

If small tidal volumes and lung volume maintenance are able

to prevent VILI in the preterm lung, then HFOV should be an
ideal mode of ventilation for preterm infants. The most
extensive animal data on this subject come from a preterm
baboon model that was characterized by Coalson and

coworkers in 1982 [2326]. Using this model, they showed

that the pathologic changes of RDS occur more commonly
after a high tidal volume and low PEEP strategy than after
HFOV using a higher mean airway pressure [25]. Hamilton
and coworkers [27] found similar results comparing HFOV
with conventional mechanical ventilation (CMV) in the salinelavaged rabbit model. More recent studies in the premature
baboon have demonstrated HFOV to be associated with
improvements in lung mechanics and histopathologic outcomes
(Fig. 1) when compared with CMV using small tidal volumes and
low PEEP [28]. Together, these animal data provide evidence
supporting both theoretical advantages of HFOV, namely
reduction in VILI associated with high tidal volumes and the
repetitive opening and closing of atelectatic units.
Another strategy to limit VILI is with a combination of
permissive hypercapnia and early extubation to CPAP. In the
preterm lamb model, 2 hours of CPAP or CMV immediately
after birth were compared; animals managed with CPAP
exhibited higher lung volumes and reduced inflammatory cell
infiltrate [28]. In the baboon CLD model, long-term
management with CPAP led to a dramatic improvement in
lung development with similar alveolarization to that in an
animal killed after normal term delivery [22].
Human studies
Before the surfactant era, Kraybill and coworkers [29]
showed that early hypocapnia was associated with a higher
incidence of BPD in a retrospective study, and after the
advent of surfactant therapy another retrospective study
found that hypocapnia before surfactant administration was
associated with similar adverse outcomes [30]. These studies
formed the basis of the hypothesis that more aggressive
ventilation might be causally related to the development of
CLD in infants. Two prospective trials of permissive hypercapnia were designed to test this hypothesis; both studies
demonstrated decreased ventilator days in the hypercapnic
group but neither found a significant difference in CLD
development, death, or development of intraventricular
hemorrhage [31,32]. Several authors have evaluated
differences in CLD prevalence among neonatal intensive care
units [3335] and concluded that ventilator strategies
designed to reduce VILI can explain these discrepancies.

Although the animal studies of HFOV support its use to

improve RDS and prevent CLD, studies in preterm infants
have not been as convincing. Many early trials did not use
prenatal steroids or surfactant, and later studies used HFOV
with low mean airway pressures and therefore did not take
advantage of the open-lung benefits of HFOV. Two large
multicenter, randomized controlled trials of early HFOV
versus CMV for the prevention of CLD in preterm infants
[36,37] were recently published simultaneously. Although
Courtney and coworkers [36] found no differences in survival
among 500 infants with birthweight under 1200 g, survival
without CLD was improved from 47% in synchronized

Available online http://ccforum.com/content/9/2/177

Figure 1

disease threshold for enrollment (mean airway pressure of at

least 6 cmH2O and 0.25 fractional inspired oxygen within the
first 4 hours of life), used more closely defined ventilator
algorithms and extubation criteria, targeted hypercapnia
(partial carbon dioxide tension 4065 mmHg) and maintained
patients on their assigned ventilator until extubation, and the
patients had a mean duration of HFOV of more than 6 days.
In contrast, Johnson and coworkers [37] did not define a
severity of illness threshold for enrollment, did not define
algorithms for ventilator management and targeted
normocapnia (partial carbon dioxide tension 3453 mmHg),
and the mean duration of HFOV was 3 days. Although
Courtney and coworkers studied a more well defined
population of infants who were sicker, the study by Johnson
and colleagues may more accurately reflect the actual
practice of HFOV across neonatal intensive care units [38].
Although the jury remains out concerning how best to
practice lung-protective ventilation in order to reduce the
incidence of CLD in preterm infants, it is clear that VILI
contributes heavily to CLD. Any successful future strategies
will undoubtedly employ the concepts of lung-protective
ventilation described above.

Gentle ventilation for persistent pulmonary

hypertension of the newborn
Full-term infants are also susceptible to the injurious effects
of mechanical ventilation. PPHN has been well recognized as
a clinical syndrome of high pulmonary vascular resistance and
right-to-left shunting since the 1950s. The responsiveness of
the pulmonary vasculature to acidbase status was
elucidated in the 1960s, and led directly to the use of
hyperventilation to produce hypocapnia and alkalosis in the
management of PPHN [39]. Two case series reported in the
early 1980s [40,41] showed that hyperventilation of infants
with PPHN increased arterial oxygen tension over several
hours. This approach was associated with reported mortality
rates of 40% in all infants and 8090% in infants with severe
PPHN [42,43].
Representative lung histopathology in (a) term baboons, (b) preterm
baboons treated with a low tidal volume, low positive end-expiratory
pressure strategy, and (c) preterm baboons treated with
high-frequency oscillatory ventilation. Hematoxylin and eosin; 100.
With permission from Yoder and coworkers [63].

intermittent mandatory ventilation-treated infants to 56% in

HFOV-treated
infants.
HFOV-treated
infants
were
successfully extubated a week earlier on average. In contrast,
Johnson and coworkers [37] found no significant differences
in overall survival or CLD among 787 infants at 2328 weeks
of gestation.
The differences in results for these two studies probably
reflect the fact that Courtney and coworkers [36] defined a

Given the emerging animal data regarding the significance of

VILI [1], Wung and coworkers [44] at Babies Hospital in
New York City began to manage PPHN without
hyperventilation in an attempt to protect the lung from high
peak inspiratory pressure and tidal volume. This was before
the advent of inhaled nitric oxide (iNO) therapy. Those
investigators reported 100% survival in 15 infants with severe
PPHN ventilated with target partial carbon dioxide tension of
4060 mmHg. Dworetz and coworkers [43] applied the
lessons from the study by Wung and coworkers, and
compared 23 infants from the era of hyperventilation versus
17 infants from the era of gentle ventilation. They found that
overall survival improved from 65% to 88% as the
management changed, and survival in the sickest infants
(who met criteria and were eligible for ECMO but did not
receive it) improved from 0% to 89%.

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Table 1
Death rates in infants with congenital diaphragmatic hernia
Period

Boston

Survival

19811984

Immediate repair without ECMO

45%

19841987

Immediate repair with postoperative ECMO

19871991
19911994

Survival

Immediate repair

53%

NS

53%

Delayed repair

52%

NS

Delayed repair, preoperative ECMO

44%

Delayed repair

52%

NS

Delayed repair, permissive hypercapnia

69%

Delayed repair, permissive hypercapnea

61%

NS

P = 0.007

Toronto

P = NS

Shown are mortality rates for infants with congenital diaphragmatic hernia (CDH) at Childrens Hospital, Boston (n = 285) and The Hospital for
Sick Children, Toronto (n = 223) during four eras of CDH management strategy. Extracorporeal membrane oxygenation (ECMO) was rarely used
for CDH at Toronto. P values were determined by students t test; P < 0.05 was considered statistically significant. NS, not significant. Adapted
from Azarow and coworkers [47].

Infants with PPHN often present with severe hypoxemic

respiratory failure, and as soon as HFOV and ECMO became
available in the late 1970s and early 1980s they were put to
use in this population of infants with very high mortality rates.
Although originally employed as a means to improve arterial
oxygen content and systemic oxygen delivery, HFOV and
ECMO also provided a means by which the lungs of these
infants could be protected from injurious mechanical
ventilation. Once iNO became available, HFOV provided a
means by which atelectatic lungs could be efficiently
recruited and enhance alveolar delivery of this selective
pulmonary vasodilator. Kinsella and coworkers [45] found
that the response to iNO therapy plus HFOV was better than
the response to iNO or HFOV alone in 205 neonates in a
randomized, controlled trial. Overall improvement in mortality
rates and reduction in need to use ECMO in these infants is
probably related to both lung-protective ventilation
(regardless of modality) and iNO therapy. Gupta and
colleagues [46] used gentle CMV with permissive hypercapnia and iNO and reported an overall mortality rate of 9.8%
in infants with meconium aspiration syndrome and PPHN a
figure comparable to that in studies combining HFOV and
iNO therapy [45].

Ventilation for congenital diaphragmatic

hernia

180

CDH is another excellent example of the negative impact that

aggressive ventilation can have on morbidity and mortality in
neonates with lung disease. Despite best efforts to improve
survival in the 1980s with delayed surgical repair and other
modern technologies such as synchronized intermittent
mandatory ventilation, HFOV, surfactant replacement, iNO,
and ECMO, mortality rates in infants with CDH remained
between 48% and 66% as recently as 1991 [47]. During this
time, management strategies included hyperventilation and
induced alkalosis in order to reduce pulmonary vascular
resistance and limit right-to-left shunting. The application of
gentle ventilation principles to the CDH population helped to
decrease mortality rates to 3139% by 1994 (Table 1)

[47,48], 20% in one center by 1998 [49], and 7% in another

center by 2002 [50].
Gentle ventilation is likely to benefit the infant with CDH
because, like the preterm lung, CDH lungs are immature and
total lung capacity is small. Even when born full term, infants
with CDH have lungs that are immature in structure and
biochemistry. Type II pneumocytes have fewer lamellar bodies
and surfactant is deficient [51]. An autopsy study found that
both alveolarization and surfactant were deficient in CDH
lungs, with the affected side being more immature than the
unaffected side [52]. An analysis of autopsy specimens from
68 out of 101 infants who died from CDH at one institution
from 1981 to 1994 showed that 91% of infants had hyaline
membrane formation, which was more prominent in the
ipsilateral, severely affected lung [49]. Of the six infants who
did not die with prominent hyaline membranes in that study,
five were treated with HFOV shortly after birth. The prominent
hyaline membranes were postulated to be a result of lung
immaturity and VILI [47,49].
Interestingly, lung disease in those survivors of CDH with
pulmonary morbidity closely resembles BPD. In a study of 45
survivors of CDH repair reported in 1993, 15 had clinical and
radiologic evidence of BPD [53]. Animal studies indicate that
the pathogenesis of VILI is similar in preterm infants and
infants with CDH. The lungs of rats with nitrofen-induced
CDH who are exposed to mechanical ventilation have
abnormally high elastin deposition [54], which is similar to
preterm lambs exposed to injurious mechanical ventilation
[55]. More abnormal deposition is present in lambs ventilated
with a slow rate and large tidal volume as compared with a
faster rate and small tidal volume [20]. Abnormal elastin
deposition is present in autopsy specimens of lungs of infants
with BPD [56,57], and abnormal layout of elastin deposition
has been proposed to play an important role in the
impairment of alveolarization seen in BPD [58]. The effects of
mechanical ventilation on elastin production and deposition
may explain impaired alveolarization in the CLD seen in both

Available online http://ccforum.com/content/9/2/177

Figure 2

Transverse T1-weighted magnetic resonance images at the level of the left atrium in (a) a 4-day-old, 26-week gestation infant, and (b) a 2-day old,
term infant. In the planes of the superimposed vertical white lines, signal intensity is graphed to the left of the images and shows that the preterm
infant has a gravity-dependent increase in signal intensity as compared with the homogeneous pattern in the term infant. The arrow in panel a
points to an area of dependent thickened pleural margin. With permission from Adams and coworkers [60].

premature infants and those with CDH. The improvements in

mortality in the era of gentle ventilation of infants with CDH
may be in part related to improved alveolar development in
these infants, but this has not yet been studied.

setting of lung disease and mechanical ventilatory support,

the young patient is likely to suffer significant alveolar
instability and atelectasis. Children with ALI/ARDS may
therefore benefit even more than adults from the lessons
learned in the animal laboratory and adult clinical trials.

Conclusion
The evidence presented above strongly supports the use of
lung-protective ventilation in the management of neonatal
lung disease. Neonates with RDS, meconium aspiration
syndrome, or CDH are thought to have more homogeneous
lung pathology than the patchy, heterogeneously aerated
pattern seen in ARDS [59], but recent magnetic resonance
imaging evidence indicates that RDS has a similar
distribution of dependent atelectasis and lung water to ARDS
(Fig. 2) [60]. This evidence gives more credence to the
concern for alveolar overdistention in the nondependent,
aerated regions of the neonatal lung. It is clear that the use of
lung-protective ventilator strategies similar to the algorithms
developed for adults with ALI/ARDS can have a significant
impact on outcomes. The non-neonate with ALI/ARDS and
heterogeneous lung mechanics may be particularly
susceptible to lung overdistension because of small absolute
lung volumes and a highly compliant chest wall. Furthermore,
large tidal volumes and elevated airway pressures in these
patients may induce regional overdistension and lung stretch
that is much more significant than in adults, whose
noncompliant chest wall and increased abdominal
compartment pressures may limit transpulmonary pressures.
In patients younger than 5 years, the closing capacity of the
lung is very close to the functional residual capacity. In the

As clinical trial networks in the pediatric population evolve

and mature [61], data relevant to the child with ALI/ARDS will
emerge. Successful design of these trials will depend on
knowledge gained from neonatal animal and human studies.
An excellent example is a recent study from Dobyns and
coworkers [62], who took lessons from the PPHN population
[45] and studied the combined effects of HFOV and iNO on
oxygenation in pediatric patients with acute hypoxemic
respiratory failure. Although a prospective, randomized,
controlled trial with important outcome measures is necessary
to draw conclusions about this therapy, data from infants with
PPHN have clearly helped to frame the important questions
about this novel therapy. In the pursuit of excellent outcomes
for children with ALI/ARDS, pediatric investigators and
practitioners alike will benefit from a thorough understanding
of relevant neonatal and adult animal and clinical data.

Competing interests
The author(s) declare that they have no competing interests.

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